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Estrogen-Induced Rat Breast Carcinogenesis is Characterized by Alterations in DNA Methylation, Histone Modifications, and Aberrant microRNA Expression

Olga Kovalchuk, Volodymyr P. Tryndyak, Beverly Montgomery, Alex Boyko, Kristy Kutanzi, Franz Zemp, Alan R. Warbritton, John R. Latendresse, Igor Kovalchuk, Frederick A. Beland and Igor P. Pogribny

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Breast cancer is the most common malignancy in women continuing to rise worldwide. Breast cancer emerges through a multi-step process, encompassing progressive changes from a normal cell to hyperplasia (with and without atypia), carcinoma in situ, invasive carcinoma, and metastasis. In the current study, we analyzed the morphological changes and alterations of DNA methylation, histone methylation and microRNA expression during estradiol-17β (E2)-induced mammary carcinogenesis in female August Copenhagen Irish (ACI) rats. E2-induced breast carcinogenesis in ACI rats provides a physiologically relevant and genetically defined animal model for studying human sporadic breast cancer. The pattern of morphological changes in mammary glands during E2-induced carcinogenesis was characterized by transition from normal appearing alveolar and ductular hyperplasia to focal hyperplastic areas of atypical glands and ducts accompanied by a rapid and sustained loss of global DNA methylation, LINE-1 hypomethylation, loss of histone H3 lysine 9 and histone H4 lysine 20 trimethylation, and altered microRNAs expression. More importantly, these alterations in the mammary tissue occurred after 6 weeks of E2-treatment, whereas the atypical hyperplasia, which represents a putative precursor lesion to mammary carcinoma in this model, was detected only after 12 weeks of exposure, demonstrating clearly that these events are directly associated with the effects of E2 and are not a consequence of the preexisting preneoplastic lesions. The results of this study show that deregulation of cellular epigenetic processes plays a crucial role in the mechanism of E2-induced mammary carcinogenesis in ACI rats, especially in the tumor initiation process.

Authors

Olga Kovalchuk

University of Lethbridge; Alberta, Canada

Volodymyr P. Tryndyak

National Center for Toxicological Research, Jefferson, Arkansas

Beverly Montgomery

National Center for Toxicological Research, Jefferson, Arkansas

Alex Boyko

University of Lethbridge; Lethbridge, Alberta, Canada

Kristy Kutanzi

University of Lethbridge; Alberta, Canada

Franz Zemp

University of Lethbridge; Lethbridge, Alberta, Canada

Alan R. Warbritton

National Center for Toxicological Research; Jefferson, Arkansas

John R. Latendresse

National Center for Toxicological Research; Jefferson, Arkansas

Igor Kovalchuk

University of Lethbridge; Lethbridge, Alberta, Canada

Frederick A. Beland

National Center for Toxicological Research; Jefferson, Arkansas

Igor P. Pogribny

NCTR; Jefferson, AR

Purchase article for $19

Subscribe to this journal for $129/year